Tardinomis — Decrypting Cryptobiosis in Tardigrades

Tardigrades are extraordinary beings that have been sent to outer space and found to survive after returning to earth. Commonly known as water bears or moss piglets, these microscopic animals are capable of surviving environmental extremes — including freezing to -230 C, ionizing radiation and total dehydration — through cryptobiosis (“hidden life”). Cryptobiosis is the reversible physiological state of an organism when it shows no sign of life, and when metabolic activity is no longer measurable. This ametabolic state is an adaptation among tardigrades that enables the animal to survive extreme conditions.

But the molecular mechanisms for preserving cellular integrity during cryptobiosis, and the genetic programs that initiate the transition in and out of cryptobiosis, are as yet unknown. Understanding this unique state of being neither dead nor alive could significantly advance the frontiers of contemporary biology, leading to new insights into the deterioration of protein homeostasis underlying human aging and several neurodegenerative disorders.

In its initial phase the project strives to sequence the genome of cryptobiotic tardigrades. The project is being led by Alwin Köhler from the Max F. Perutz Laboratories at the Vienna Biocenter in Austria.

Tony Wyss-Coray, NOMIS Distinguished Scientist Awardee 2017

Tony Wyss-Coray, professor of neurology and neurological sciences at Stanford University, California, investigates the role of immune responses in brain aging and neurodegeneration with a focus on cognitive decline and Alzheimer’s disease. His most recent studies have shown that circulatory factors can modulate neurogenesis, neuroimmunity and cognitive function in mice and that blood-derived factors from young mice or humans can rejuvenate the aging mouse brain. The Wyss-Coray lab is now trying to understand the molecular basis of this systemic communication with the brain by employing a combination of omics approaches and through the development of bioorthogonal tools for the in vivo labeling of proteins.

The NOMIS Distinguished Scientist Award is enabling Wyss-Coray and his team to test the hypothesis that circulatory factors that regulate aging can be identified and used to rejuvenate aged and possibly degenerated brains. His lab will use mass spectrometry and proteomic technologies in combination with a new short-lived fish model — the African turquoise killifish, which has been established as the shortest-lived vertebrate aging model by Anne Brunet, professor of genetics at Stanford University and one of the partners of this project — and unique human clinical material. The project seeks to advance the understanding of the basic biology of aging.

In an interview with NOMIS, we asked Wyss-Coray about what drove him to become a scientist and the challenges insight-driven research in his field is facing. Read the complete interview.

Tony Wyss-Coray received a PhD in immunology at the University of Bern, Switzerland, in 1992. He spent his postdoctoral years at the Scripps Research Institute in California and was appointed professor for the Department of Neurology and Neurological Sciences at Stanford University in 2011.

For more information about Tony Wyss-Coray and his research please see his faculty profile.

Karl Deisseroth, NOMIS Distinguished Scientist Awardee 2017

Karl Deisseroth is D.H. Chen Professor of Bioengineering and of Psychiatry and Behavioral Sciences at Stanford University, California. He has been credited with developing and implementing an approach to biology called optogenetics, a technique that involves the use of light to control cells in living tissue, typically neurons, that have been genetically modified to express light-sensitive ion channels. Among other advances in laboratory neuroscience techniques, his research has led to thousands of major discoveries regarding the causal underpinnings of complex behavior. But while optics-based discovery of causal mechanisms in animals has been successful, little work has succeeded in revealing brain-wide patterns and underlying causal principles in humans.

The NOMIS Distinguished Scientist Award 2017 enables Deisseroth and his team to implement the project Circuit States: Discovering the Causal Principles Underlying Brain-wide Dynamics, which will adapt and combine new technologies developed in the Deisseroth Lab. Among them is CAPTURE, a technique that combines optogenetics and another recently developed technique, CLARITY, to see into the intact brain, enabling highly detailed pictures of the protein and nucleic acid structure of the brain to be taken. CAPTURE makes it possible to track brain-wide networks of cells that were actively engaged during behavioral experiments.

The aim of adapting these new techniques is to record and control thousands of neurons across multiple brain areas. Based on the results, the project will build causal models for brain-wide neurodynamics in behavior as well as for brain states corresponding to acute or chronic stress and to multisensory integration in attention-requiring discrimination. Deisseroth’s research project has the potential to unify different areas of biology, and significantly advance our basic understanding of neural pathways.

In an interview with Deisseroth, NOMIS talked to him about how he builds an environment that fosters creative science and what kind of people he needs on his team to do pioneering research. Read the complete interview.

Karl Deisseroth studied biochemical science at Harvard University, Boston, and received a PhD in neuroscience in 1998 and an MD in 2000 from Stanford University. He was appointed D.H. Chen Professor of Bioengineering and of Psychiatry and Behavioral Sciences at Stanford University in 2012.

Svante Pääbo, NOMIS Distinguished Scientist Awardee 2017

Svante Pääbo, director of the Department of Evolutionary Genetics at the Max Planck Institute in Leipzig, Germany, is one of the founders of paleogenetics and became best known for his pioneering research on the Neandertal genome. His interest in molecular biology, molecular genetics and Egyptology were the reason for his efforts to clone nuclear DNA from an Egyptian mummy as early as 1985, which established him in the field of evolutionary genetics at a very young age. In 2009, he and his team had completed the first draft of the Neandertal genome, opening up a whole new field of research into the history of modern humans.

The NOMIS Distinguished Scientist Award 2017 supports Pääbo in his quest to learn more about the genetic differences and functional consequences that occurred at the split between the modern human and their archaic human ancestors about half a million years ago. Findings will represent a crucial first step toward understanding the genetic underpinnings of the human condition and thus provide an additional inroad to study diseases and other conditions that affect traits that are unique to humans.

NOMIS interviewed Pääbo about what makes a productive research environment, how pushing scientific boundaries might reflect certain personality traits and what influence his research might have beyond the borders of his own scientific fields. Read the full interview.

Svante Pääbo earned his PhD from Uppsala University in 1986. He did his postdoctoral research at the Department of Biochemistry at the University of California at Berkeley, United States, and became professor of general biology at the University of Munich, Germany, in 1990. In 1997 he was appointed director of the Department of Evolutionary Genetics at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

“… it is only in an environment in which you feel safe and at ease that you dare to express crazy ideas — there is nothing more stifling than fear.”

Svante Pääbo studies DNA preserved in the remains of ancient organisms and what it can tell us about human evolution. NOMIS supports his investigation of the changes that occurred in human proteins involved in the development and function of nerve cells during the past half-million years. This project is a crucial first step toward understanding the genetic underpinnings of what makes modern humans unique.

Svante Pääbo is a NOMIS Distinguished Scientist Awardee and the director of the Department of Evolutionary Genetics at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. We spoke with him about his career and about how he creates a unique working environment in his group.

 

NOMIS: You were still a PhD student when your research was published in Nature. Did this early success trigger your interest in a research career?

SP: I do not think that success per se was important. What was crucial was rather my fascination with ancient history and Egyptology. This meant that when I got into molecular biology it seemed natural to apply this to ancient remains, which I knew were lying around in museums.

NOMIS: Your mother was a scientist; did this influence you?

SP: Growing up with my mother, who was a chemist, instilled in me a feeling that research is cool and interesting. That surely influenced me.

NOMIS: Other scientists have referred to you as a role model with respect to team-leading. Do you know why?

SP: [Laughs] You should ask my team if this is really true…

NOMIS: But how do you create a productive research environment?

SP: I — like everyone else — want to have fun. I want enjoy being at my workplace and want to work with people who also have fun. That is not always possible, but we try to create an environment where one can have a good time.

NOMIS: What are your criteria for selecting candidates to be on your team?

SP: We try to involve the group in all decisions, including the decision about who gets hired. When we recruit students, postdocs or group leaders, they get to talk to almost everybody. After that, we discuss how the candidates would fit in scientifically as well as socially. It is very important that people get along, because it is only in an environment in which you feel safe and at ease that you dare to express crazy ideas — there is nothing more stifling than fear.

NOMIS: What about grades — are they informative to you?

SP: Someone who has perfect grades in every subject makes me a little suspicious — not that we would refuse to interview someone like that, but I would want to explore whether they have passions or interests. Someone who is very good in certain subjects but perhaps mediocre in others is more what we may look for.
But above all, it is important that somebody can explain, for example, what they did in their Masters thesis. Do they think critically about it? That is much more important than if they have been lucky with their project and produced a fancy paper.

It is also important that they have thought about what we are doing, and perhaps even propose experiments that could be done — even if these are things that an insider knows are not realistic.

NOMIS: Was your environment supportive of you in terms of pursuing your research?

SP: At the time when I was working on my PhD, it became obvious that one could address a lot of evolutionary questions by applying the then-new techniques of cloning DNA in bacteria to present-day organisms. One could, for example, find out how different species were related to each other. To me, it was very tempting to try to “go back in time” to see what DNA sequences were around thousands of years ago. But I was not sure that my PhD supervisor would be supportive of this, so I initially kept it secret. Nevertheless, the environment was certainly supportive in that there were enough resources around to try crazy things like this, things that had only a remote chance of success.

NOMIS: In retrospect, what was the most difficult period of your research career?

SP: The preservation of DNA from ancient mummies and other dead organisms quickly led me to believe that we could address all kinds of interesting questions. But then came the realization that many of the DNA sequences that were retrieved, including those first sequences from an Egyptian mummy, which I published, came from present-day human DNA in the environment, and not from the ancient organisms. For example, our group showed that if you extracted DNA from an ancient mammoth or cave bear, you could almost always get human DNA from it, and only rarely elephant-like or bear-like DNA. This human DNA came from museum keepers, from archaeologists or from ourselves.

For a number of years we thought that any work on ancient DNA would have to be restricted to extinct animals, because in these cases human DNA contamination could be easily recognized as such. That was disappointing to me as I was really interested in human history and human evolution. Fortunately, this changed when new techniques were developed. And over the past ten years, it seems that all my wild dreams from 30 years ago are coming true.

NOMIS: Do you think that your research influences current paradigms within philosophy or social science?

SP: “Paradigm” is a grand word. I leave that to others… Perhaps the fact that Neandertals contributed genetically to present-day humans has influenced how people think about Neandertals. Yet, how people speculate about the interaction between these two forms of humans says much more about the person speculating and almost nothing about what happened tens of thousands of years ago. Some would view the disappearance of Neandertals as the first genocide committed by modern humans; others would focus on what was perhaps peaceful coexistence for many thousands of years. What really happened, we do not know.

NOMIS: As a scientist you are constantly pushing the envelope. Does this in any way reflect a personality trait? Are you a risk taker?

SP: As a scientist you are, in my opinion, an extremely privileged person: You are paid a salary for playing around with ideas you find interesting — it is amazing. So what we do is not really “risk taking” in my mind. But many scientists who open up new fields may perhaps have a certain irreverence for the received wisdom. Maybe they even take a delight in questioning what everyone else believes. They may have a certain disrespect for authority.

This interview was conducted by Cosima Crawford on Feb. 15, 2017.

“Success, at least the kind that I want to see — the creativity, the brilliance, the vision — can’t be told from bibliometric indicators or grades.”

Karl Deisseroth, recipient of the NOMIS Distinguished Scientist and Scholar Award and D.H. Chen Professor of Bioengineering and of Psychiatry and Behavioral Sciences at Stanford University, California, is known for launching an approach to biology called optogenetics, a technique that makes it possible to directly control, with single-cell resolution, the real-time activity of specific cells deep within living animals that are carrying out complex behaviors. His research has led to the discovery of the specific cellular activity mechanisms that control anxiety, social behavior, aggression, memory and many other complex cognitions and behaviors.

We spoke with Deisseroth at his off-site CNC lab in Stanford, California, about what it is that excites him about the brain, about researchers who have inspired him, and about how to break out of major paradigms and enable new approaches in science.

 

NOMIS: What sparked your interest in the human brain?

KD: I always wondered how an object could give rise to such subjective things like emotions and feelings. To me, that was always a mystery, which was at a par with many big mysteries of the world. From early on, that has been an interesting question.

I also discovered that words, rhythms and poetry affect feelings. And I got very interested in writing. When I went to college, I thought I would become a writer — it was interesting and also very uplifting to realize that you can affect feelings with words.

But it was really in college, with a mix of engineering and biology classes, that I discovered that there was a compelling way to approach this question. I started as a biochemist and learned how similarly challenging problems such as cancer and its development have been addressed with real biochemical work and I thought, “This is what I’ll try to do.” But I ultimately wanted to know about the human brain, which is why I did an MD/PhD.

NOMIS: Do you have any role models who influenced the way you do research today?

KD: My mentors were wonderful. My parents were influential. But I never had a person whose style I followed. There have been people for whom I have great respect. I admired the nature of Christiane Nüsslein-Volhard’s approach: tackling a seemingly intractable question by building the right tools and finding the right level at which the system can be addressed — and then adding very rigorous and creative biology.

The other person whose approach I found admirable is Santiago Ramón y Cajal, a Spanish neuroscientist. Again, very systematic, both building and using the best tools and, through rigorous work and deep thinking, he created the whole foundation for neuroscience.

NOMIS: Science is collaborative; doing science successfully implies finding the right people and getting them to work together. Do you find that difficult?

KD: Each scientist has a different set of skills and personal traits; what works for some people does not work for others. I do know pretty well what I can do and where I need somebody else’s skills. Figuring that out was a big part of my training.

But the biggest challenge was bringing together biologists and engineers because they have a very different way of looking at problems and even defining problems. Being at that interface between engineering and biology was important and required a lot of thinking, planning and keeping everyone together and talking.

NOMIS: Is there a lesson you have learned from building interdisciplinary teams that might apply not only in your specific case but in general?

KD: A common occurrence in an interdisciplinary environment is that the initial conversations are awkward and difficult. You have to know this will happen and that people won’t necessarily understand or even respect each other, because they have such different ways of thinking, as well as different priorities and approaches. If you want to make it work you have to set up a situation to get people through these first moments. That is something I’ve worked hard on.

NOMIS: Was setting up one of your labs off campus a part of the solution?

KD: Partly, yes. I knew the lab needed to grow and I wanted to have a protected space where people would not be swept along with the paradigm that was going on in the main lab — that is, a very clear, productive pathway to wonderful science. But it was such a strong paradigm that it was very hard to do something completely new because people would easily get plugged into that pathway. So setting up a situation that was protected was crucial to making it work, and that was the off-campus location.

NOMIS: Your scientific questions overstep the comfort zone of established methodological approaches. Implementing them bears the potential of great discoveries but it also implies a high risk of failure. How do you perceive and deal with that risk?

KD: I don’t like taking risks in my personal life, but scientifically I do. I structure my work such that it absorbs the shock of failure and therefore enables risk taking — in a way “de-risking” risky experiments. One way to do this is to identify the personalities that get completely involved in the science and do not hold back in view of potential failure. I select people who are at the appropriate career stage and have a record of past successes. Based on this security they have the mental strength to try out new things. This was, for example, how we managed to implement the CLARITY project. I told the team, “If this works out, it is going to be huge; but if it doesn’t, you are fine.”

NOMIS: Speaking of personalities, do you have explicit criteria for deciding with whom you want to work?

KD: Success, at least the kind that I want to see — the creativity, the brilliance, the vision — can’t be told from bibliometric indicators or grades. Partly it is their passion that convinces me. I want to see in their science and in what they have done, the love, the thrill, the excitement of the science. I ask myself, “Is this the sort of person who goes to sleep thinking about a problem and wakes up thinking about the problem?”

But it is also establishing whether people have the right level of ego to work in a group or to be collaborative, who do not have too many personal issues that keep them from forming good collaborations and being part of a team. I bring a little bit of the psychiatrist to these discussions.

NOMIS: Besides a lot of praise, your work has raised ethical questions as well. Is this a topic you contemplate?

KD: We and others have used optogenetics to determine how behaviors such as anxiety, social behavior, aggression and memory are elicited and controlled, and we now know how to turn up or down these mechanisms. That creates very interesting issues — not ethical but philosophical — with regard to free will and possible options for actions. At the moment, nobody is trying to modify human behavior, and even looking forward, it is not an issue that I am worried about in its direct, explicit form, but it is a topic, conceptually.

I can’t say I have solved some philosophical problem. All I can say is, I have done something to make the problem clearer.

This interview was conducted by Cosima Crawford on January 23, 2017.